The purpose of this study was to determine the reproducibility of dynamic contrast-enhanced (DCE)-MRI and compare quantitative kinetic parameters with semi-quantitative methods, and whole region-of-interest (ROI) with pixel analysis. Twenty-one patients with a range of tumour types underwent paired MRI examinations within a week, of which 16 pairs were evaluable. A proton density-weighted image was obtained prior to a dynamic series of 30 T 1 -weighted spoiled gradient echo images every 11.9 s with an intravenous bolus of gadopentetate dimeglumine given after the third baseline data point. Identical ROIs around the whole tumour and in skeletal muscle were drawn by the same observer on each pair of examinations and used for the reproducibility analysis. Semiquantitative parameters, gradient, enhancement and AUC (area under the curve) were derived from tissue enhancement curves. Quantitative parameters (K trans , k ep , v e ) were obtained by the application of the Tofts' model. Analysis was performed on data averaged across the whole ROI and on the median value from individual pixels within the ROI. No parameter showed a significant change between examinations. For all parameters except K trans , the variability was not dependent on the parameter value, so the absolute values for the size of changes needed for significance should be used for future reference rather than percentages. The size of change needed for significance in a group of 16 in tumours for K trans , k ep and v e was À14 to 16%, AE0.20 ml/ml/min (15%) and AE1.9 ml/ml (6%), respectively (pixel analysis), and À16 to 19%, AE0.23 ml/ml/min (16%) and AE1.9 ml/ml (6%) (whole ROI analysis). For a single tumour, changes greater than À45 to 83%, AE 0.78 ml/ml/min (60%) and AE 7.6 ml/ml (24%), respectively, would be significant (pixel analysis). For gradient, enhancement and AUC the size of change needed for significance in tumours was AE0.24 (17%), AE0.05 (6%) and AE0.06 (8%), respectively for a group of 16 (pixel analysis), and AE0.96 (68%), AE0.20 (25%) and AE0.22 (32%) for individuals. In muscle, the size of change needed for significance in a group of 16 for K trans , k ep and v e was À30 to 44%, AE0.81 ml/ml/min (61%) and AE1.7 ml/ml (13%). For gradient, enhancement and AUC it was AE0.09 (20%), AE0.02 (8%) and AE0.03 (12%). v e , enhancement and AUC are highly reproducible DCE-MRI parameters. K trans , k ep and gradient have greater variability, with larger changes in individuals required to be statistically significant, but are nevertheless sufficiently reproducible to detect changes greater than 14-17% in a cohort of 16 patients. Pixel analyses slightly improve reproducibility estimates and retain information about spatial heterogeneity. Reproducibility studies are recommended when treatment effects are being monitored.

Purpose: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) allows noninvasive, in vivo measurements of tissue microvessel perfusion and permeability. We examined whether DCE-MRI done after two cycles of neoadjuvant chemotherapy could predict final clinical and pathologic response in primary breast cancers. Experimental Design: Thirty-seven patients with primary breast cancer, due to receive six cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy, were examined using DCE-MRI before neoadjuvant chemotherapy and after two cycles of treatment. Changes in DCE-MRI kinetic parameters (K trans , k ep , v e , MaxGd, rBV, rBF, MTT) were correlated with the final clinical and pathologic response to neoadjuvant chemotherapy.Test-retest variability was used to determine individual patient response. Results: Twenty-eight patients were evaluable for response (19 clinical responders and 9 nonresponders; 11 pathologic responders and 17 nonresponders). Changes in the DCE-MRI kinetic parameters K trans , k ep , MaxGd, rBV, and rBF were significantly correlated with both final clinical and pathologic response (P < 0.01). Change in K trans was the best predictor of pathologic nonresponse (area under the receiver operating characteristic curve, 0.93; sensitivity, 94%; specificity, 82%), correctly identifying 94% of nonresponders and 73% of responders. Change in MRIderived tumor size did not predict for pathologic response. Conclusion: Changes in breast tumor microvessel functionality as depicted by DCE-MRI early on after starting anthracycline-based neoadjuvant chemotherapy can predict final clinical and pathologic response. The ability to identify nonresponders early may allow the selection of patients who may benefit from a therapy change.

CA4P acutely reduces Ktrans in human as well as rat tumors at well-tolerated doses, with no significant changes in kidney or muscle, providing proof of principle that this drug has tumor antivascular activity in rats and humans.

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O 2 , 5% CO 2 ). T* 2 -weighted gradient-echo imaging was performed before, during, and after carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty-six successful tumor examinations were obtained. Twenty showed significant whole-tumor signal increases (mean 21.0%, range 6.5-82.4%), and one decreased (؊26.5 ؎ 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4 -14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 ؎ 3.7%, range 5.0 -11.7%). T* 2 -weighted tumor MRI during carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from carbogen radiosensitization.

Purpose: The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.Experimental Design: Patients with advanced solid malignancies received CA4P at 45, 54, or 63 mg/m 2 on day 1, day 8, and then every 14 days. Bevacizumab 10 mg/kg was given on day 8 and at subsequent cycles four hours after CA4P. Functional imaging with dynamic contrast enhanced-MRI (DCE-MRI) was conducted at baseline, after CA4P alone, and after cycle 1 CA4P þ bevacizumab.Results: A total of 63 mg/m 2 CA4P þ 10 mg/kg bevacizumab q14 is the recommended phase II dose. A total of 15 patients were enrolled. Dose-limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage. Most common toxicities were hypertension, headache, lymphopenia, pruritus, and pyrexia. Asymptomatic electrocardiographic changes were seen in five patients. Nine of 14 patients experienced disease stabilization. A patient with ovarian cancer had a CA125 response lasting for more than a year. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability, which reversed after CA4P alone but which were sustained following bevacizumab. Circulating CD34 þ and CD133 þ bone marrow progenitors increased following CA4P as did VEGF and granulocyte colony-stimulating factor levels. Conclusions: CA4P in combination with bevacizumab appears safe and well tolerated in this dosing schedule. CA4P induced profound vascular changes, which were maintained by the presence of bevacizumab.